Inflammations are complex reactions characterized by interactions between a variety of factors, which are mainly associated with leukocytes. Inflammatory stimuli cause migration of leukocytes to a site of stimulation via venules. In acute inflammation, neutrophils first infiltrate such a site and infiltration by macrophages and lymphocytes follows. Depending on the type of inflammation, infiltration of eosinophils and basophils also occurs. Infiltration between these leukocytes varies depending on the type of inflammation and so does the duration of infiltration; hence, different mechanisms have been proposed for the respective leukocytes.
The infiltration of neutrophils is also a complex phenomenon. It is said that, neutrophils normally flow in the center of the blood stream. But when a stimulus is exerted, it causes an increase in the microcirculation and a decrease in the rate of blood flow, thereby the neutrophils reach to the blood vessel wall and flow there in accordance with the mechanism of fluid dynamics, eventually coming into contact with vascular endothelium. At the early stage, neutrophils roll over and move slowly, as if they walk along the surface of endothelial cells. Then, they adhere (bind) firmly to the endothelial cells. The adherent neutrophils extrude pseudopodia toward the site where they bind to endothelial cells and the endothelial cells also surround the neutrophils. The neutrophils then extend toward the subendothelial cavity, pass through the vascular adventitial (perithelial) cells, and finally infiltrate into the tissues. At a site where the inflammatory stimulative foreign body exists, neutrophils exhibit their functions, through production of active oxygen, secretion of degradative infiltration enzymes, release of cytokines and phagocytosis.
The infiltration of neutrophils is not limited to the case of invasion of foreign bodies, such as viruses and bacteria. At the time myocardial infarction or an organ transplant occurs and, the blood flow into the organ is recovered, organ injuries accompanied by the infiltration of neutrophils sometimes occur. This symptom is called ‘ischemic reperfusion injury’.
Neutrophils are considered to respond to the chemotactic factors, which are produced at a site of inflammation, and move to the site by recognizing the density gradients of those factors. Factors (chemotactic factors) known to date are capable of inducing the migration of neutrophils to a local site. They are a series of proteinaceous factors called ‘chemokines’, ‘complement factors C3a and C5a’, a factor in the metabolism of arachiodonic acid ‘leukotriene B4’, and other factors, such as ‘platelet-activating factors’ and formyl peptides including formyl methionyl-leucyl-phenylalanine (fMLF), which is a model peptide of bacterial proteins (Annu. Rev. Immunol. 2, 257-281, 1984 and Annu. Rev. Immunol. 15, 675-705, 1997). However, it is not completely clear how these substances are involved at the stage of inflammation.
‘Chemokine(s)’ are the collective term for proteinaceous endogenous substances that are capable of causing neutrophils, monocytes, T lymphocytes, etc. to migrate to local sites. ‘Chemokines’ are classified into four families according to their primary structures, including a CC family (1), in which the first and second cysteine residues from the N terminus are aligned adjacent to each other, a CXC family (2), in which the two cysteine residues are separated by one amino acid, a CX3C family (3), in which the two cysteine residues are interrupted by three amino acids, and a C family (4), having one cysteine residue. Among these families, only the CXC family is considered to act on neutrophils and chemokines known to belong to this family include interleukin-8 (IL-8), neutrophil activating protein-2, etc. (Annu. Rev. Immunol. 15, 675-705, 1997).
It is also known that at the site of inflammation, the active oxygen, degradative enzymes and other substances that are released by activated neutrophils cause the cell injury. Since the concentrations of various chemokines including IL-8 are elevated in the tissues affected by such injuries, it is said that IL-8 and other chemokines are also involved in the tissue destruction by the activated neutrophils. However, it is hard to believe that IL-8 is involved at the stage where the cell injury occurs.